Patients diagnosed with oral squamous cell carcinoma (SCC) continue to face significant morbidity and mortality. Although the risk-factors of oral SCC are known, the molecular mechanisms responsible for this dreadful malignancy remain unclear. In particular, the molecular basis of the invasive growth properties of oral SCC is not well understood. We have previously found that HGF/c-Met signaling promotes the malignant progression of oral SCC through the activation of multiple downstream signaling molecules. Our new research suggests a role for Yes-associated protein (YAP) in HGF/c-Met-stimulated oral SCC invasive growth. We hypothesize that YAP functions in HGF/c-Met-induced invasive growth by regulating the transcription of select genes necessary for invasion and metastasis. Our proposal is to use gene microarrays to identify YAP- regulated genes and to use molecular and genetic techniques to investigate whether these genes regulate the induction of invasive genes by HGF. Immunohistochemistry will be performed to evaluate the expression of YAP and other proteins in oral SCC tissues. The mechanism whereby YAP is regulated in response to HGF stimulation will also be investigated. Our main goals are to determine how YAP regulates SCC cell invasive growth and whether YAP is involved in human SCC invasion and metastasis. There are three specific aims for this project. In Aim1, the mechanism whereby YAP functions in oral SCC invasive growth and the relevance of YAP to human SCC will be investigated. In Aim 2, the signaling events leading to YAP regulation by HGF will be elucidated. In Aim 3, a role for YAP in SCC anoikis resistance will be examined. These studies will be expected to provide greater insight into the molecular regulation of oral SCC and the development of new therapeutic approaches. PUBLIC HEALTH RELEVANCE: The research outlined in this K99/R00 award will reveal new details about the molecular basis of oral carcinogenesis. The ultimate goal of this work is to improve our understanding of the propensity of oral cancer cells to invade tissues and metastasize so as to improve our options for therapeutic intervention.